TNFRSF10B - TNF receptor superfamily member 10b | Elisa - Clia - Antibody - Protein

Background

TNFRSF10B (TNF receptor superfamily member 10b), also known as TRAIL-R2, DR5 (death receptor 5), or KILLER (Killer/DR5), is a cell surface receptor in the TNF receptor superfamily. It plays a crucial role in mediating apoptosis, especially in transformed or cancerous cells, through interaction with the TNF-related apoptosis-inducing ligand (TRAIL). Like other members of the death receptor family, TNFRSF10B is part of the body's natural mechanism for controlling cell growth, immune responses, and tumor suppression. TRAIL selectively targets cells exhibiting TNFRSF10B expression, making it a key pathway in immune surveillance and tumor inhibition, while leaving normal cells relatively unaffected. Due to its selective induction of apoptosis in abnormal cells, TNFRSF10B has become an important target in cancer therapeutics.

Protein Structure

The TNFRSF10B protein is a type I transmembrane receptor that shares a similar structural organization with other death receptors. The structure consists of the following domains:

Extracellular Domain (ECD):

• The ECD of TNFRSF10B contains three cysteine-rich domains (CRDs), which are responsible for ligand binding. This region is involved in the high-affinity interaction with TRAIL, facilitating receptor activation. The cysteine residues in this domain form disulfide bonds, giving the ECD structural stability and the ability to oligomerize upon ligand binding.
• The extracellular domain is critical for the selective binding of TRAIL, which is essential in TRAIL-induced apoptotic signaling.

Transmembrane Domain (TMD):

• The transmembrane domain of TNFRSF10B anchors the receptor in the plasma membrane. This domain spans the lipid bilayer and is essential for maintaining the receptor's localization on the cell surface. The transmembrane region also helps stabilize receptor conformation, enabling proper interaction with TRAIL and subsequent oligomerization.

Intracellular Death Domain (DD):

• The death domain is a conserved region within the cytoplasmic tail of TNFRSF10B that is responsible for transducing apoptotic signals. Upon TRAIL binding and receptor oligomerization, the death domain recruits adaptor molecules, primarily FADD (Fas-associated death domain), leading to the formation of the death-inducing signaling complex (DISC).
• The formation of the DISC subsequently activates caspase-8 and initiates the downstream apoptotic cascade, which ultimately results in cell death. This domain is essential for the receptor's function in inducing apoptosis, making it a target for regulation in both cancer cells and therapeutic interventions.

Classification and Subtypes

TNFRSF10B is a member of the TNF receptor superfamily, specifically classified as a death receptor due to its ability to directly induce apoptosis through its intracellular death domain. It shares significant structural and functional similarity with TNFRSF10A (also known as TRAIL-R1 or DR4), another death receptor for TRAIL. Although both receptors can initiate apoptosis, their distribution and relative affinities for TRAIL may vary slightly, influencing their roles in specific cell types or tissues.

Within the death receptor family, there are also decoy receptors such as DcR1 (TRAIL-R3) and DcR2 (TRAIL-R4), which bind TRAIL but lack functional death domains, rendering them unable to induce apoptosis. These decoy receptors regulate TRAIL signaling by competing for ligand binding with TNFRSF10B, modulating apoptotic sensitivity in cells.

Function and Biological Significance

Apoptosis and Cell Death:

• TNFRSF10B plays a primary role in apoptosis. Upon binding TRAIL, TNFRSF10B undergoes a conformational change, leading to receptor oligomerization and DISC formation. This, in turn, activates caspase-8, which initiates the extrinsic apoptotic pathway. The activation of caspase-8 can also engage the intrinsic (mitochondrial) apoptotic pathway, enhancing the cell death signal.
• This receptor-mediated apoptosis is particularly significant in removing cancerous, infected, or otherwise abnormal cells, allowing for controlled cell turnover and prevention of malignancies.

Tumor Surveillance:

• TNFRSF10B is essential in immune-mediated tumor surveillance, where immune cells such as NK (natural killer) cells and T cells express TRAIL to target and eliminate cancer cells expressing the receptor. This TRAIL-mediated apoptosis pathway is one of the ways the immune system limits tumor development and spread.

Immune Regulation and Inflammatory Response:

• Besides apoptosis, TNFRSF10B contributes to immune regulation by influencing the activity of various immune cells. It helps regulate inflammation, providing a mechanism for terminating immune responses and preventing excessive tissue damage.
• TRAIL and TNFRSF10B signaling pathways have been shown to impact inflammatory processes in autoimmune conditions, making it a potential target in managing diseases where immune dysregulation plays a role.

Clinical Issues

Cancer Therapy:

• TNFRSF10B has been widely studied as a target for cancer therapy due to its role in inducing apoptosis selectively in cancer cells. Therapeutic approaches include recombinant TRAIL proteins, agonistic antibodies, and TRAIL-R2 targeting agents that activate TNFRSF10B.
• However, resistance to TRAIL-induced apoptosis has been observed in various cancers, often due to mutations in TNFRSF10B, upregulation of anti-apoptotic proteins (e.g., FLIP, Bcl-2), or the presence of decoy receptors. Overcoming these resistance mechanisms is an active area of research, with combination therapies and targeted drugs being developed to enhance the therapeutic efficacy of TNFRSF10B activation in tumors.

Autoimmune and Inflammatory Diseases:

• TNFRSF10B signaling is implicated in autoimmune disorders and chronic inflammatory diseases. Dysregulation of TRAIL or TNFRSF10B can lead to inappropriate cell survival or cell death, contributing to pathologies where immune cells target self-tissues.
• Research into modulating TNFRSF10B activity in autoimmune diseases is ongoing, as regulating TRAIL signaling could offer therapeutic benefits by balancing apoptosis and cell survival in immune cells.

Viral Infections and Immune Evasion:

• Some viruses have evolved mechanisms to evade TNFRSF10B-mediated apoptosis by downregulating the receptor on infected cells or inhibiting TRAIL binding. This evasion allows for viral persistence, contributing to chronic infection. Targeting TNFRSF10B signaling in such infections may enhance immune clearance of infected cells.

Summary

TNFRSF10B, or TRAIL-R2, is a death receptor in the TNF receptor superfamily known for its key role in inducing apoptosis, particularly in cancerous and abnormal cells. The receptor’s structure, including its cysteine-rich extracellular domain, transmembrane domain, and intracellular death domain, is optimized for binding TRAIL and initiating the apoptotic cascade. TNFRSF10B’s functions extend beyond apoptosis, playing roles in immune regulation, tumor suppression, and inflammatory responses, making it a central component of immune surveillance and immune homeostasis.

In cancer therapy, TNFRSF10B is targeted through various strategies aimed at activating its apoptotic pathway in tumor cells, although resistance mechanisms remain a challenge. The receptor is also involved in immune regulation in autoimmune and inflammatory diseases, highlighting its importance across a range of clinical applications. Research into optimizing the therapeutic activation of TNFRSF10B continues to explore its potential in oncology and immunology, balancing apoptosis induction with therapeutic precision to harness its selective cell-killing properties.